An Injectable and Drug-loaded Supramolecular Hydrogel for Local Catheter Injection into the Pig Heart

Abstract

Regeneration of lost myocardium is an important goal for future therapies because of the increasing occurrence of chronic ischemic heart failure and the limited access to donor hearts. An example of a treatment to recover the function of the heart consists of the local delivery of drugs and bioactives from a hydrogel. In this paper a method is introduced to formulate and inject a drug-loaded hydrogel non-invasively and side-specific into the pig heart using a long, flexible catheter. The use of 3-D electromechanical mapping and injection via a catheter allows side-specific treatment of the myocardium. To provide a hydrogel compatible with this catheter, a supramolecular hydrogel is used because of the convenient switching from a gel to a solution state using environmental triggers. At basic pH this ureido-pyrimidinone modified poly(ethylene glycol) acts as a Newtonian fluid which can be easily injected, but at physiological pH the solution rapidly switches into a gel. These mild switching conditions allow for the incorporation of bioactive drugs and bioactive species, such as growth factors and exosomes as we present here in both in vitro and in vivo experiments. The in vitro experiments give an on forehand indication of the gel stability and drug release, which allows for tuning of the gel and release properties before the subsequent application in vivo. This combination allows for the optimal tuning of the gel to the used bioactive compounds and species, and the injection system.

Self-Healing Supramolecular Hydrogels Based on Reversible Physical Interactions

“…They also provide a specific biological and mechanical three-dimensional environment for cells that guides the regulation of cellular functions during the formation of regenerated tissue. Injection delivery can be done via a syringe or via a catheter and recently, an H-bonded UPy-unit containing hydrogels loaded with a small-molecule drug pirfenidone or a fluorescent model protein mRuby2 were injected into a pig heart via an intramyocardial catheter [175]. The injectable system was a Newtonian fluid with low viscosity at high pH and formed a stiff gel with G′ = 10–20 kPa (at angular frequency ω = 0.1–100 rad/s) after neutralization.…”

Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart

“…In addition to cardiac bulking, injectable hydrogels have been designed for the therapeutic delivery of biologically active agents to the heart, which include growth factors[13,14], small molecules[15], DNA[16], and RNA [17,18]. Through a combination of diffusion, erosion, and swelling, hydrogels can release encapsulated therapeutics, with kinetics that are tuned by varying features such as polymer concentration, crosslink density, and drug-polymer interactions (e.g.…”

Alleviation of renal ischemia/reperfusion injury by exosomes from induced pluripotent stem cell-derived mesenchymal stem cells

“…However, several studies showed that exosomes have a short half-life in vivo [42,43], limiting their therapeutic potential for clinical application. Various forms of hydrogels such as chitosan/silk hydrogel, chitosan hydrogel, and imine crosslinking hydrogel have been used to enhance the therapeutic effects of exosomes [44][45][46][47]. Finally, secreted EVs can be eliminated as cellular waste.…”